The regulation and genomic organization of the family of UDP- glucuronosyltransferase enzymes are being studied at the RNA, DNA and protein levels in mice and human. An undetermined number of transferase activities is involved in detoxifying through the glucuronidation of numerous lipophiles. Induction of certain activities is known to be effector-specific. An expression system developed in Saccharomyces cerevisiae (pEVPll vector) shows that sequenced and full-coding mouse transferase cDNA encodes a 51 KDa transferase protein. The endoplasmic reticulum-bound enzyme specifically glucuronidates naphthol, estrone, p-nitrophenol, phenolphthalein 4-methylumbelliferone, dihydrotestosterone, androsterone, and testosterone. Upon removal of the membrane- targeting signal peptide coding region of the cDNA, the truncated insert expresses a cytosolic protein which catalyzes the glucuronidation of naphthol primarily and that of 3- hydroxybenzo(a)pyrene only weakly. A human full-coding transferase cDNA was sequenced and determined to be polymorphic containing six amino acid differences (including a Stu I restriction site change when compared to a sequenced, but otherwise, uncharacterized human transferase cDNA recently published). This form hybridizes to both a 2600- and a 3600-base human mRNA species. Furthermore, mRNA isolated from the excised liver of a Crigler-Najjar patient (who successfully underwent a liver transplant) has reduced hybridization to this form. Yeast transformed with pAAH5 containing this human cDNA insert synthesizes a 50 KDa transferase protein. Studies are underway to determine substrate specificity.